Valsartan is chemically described as (S)—N-(1-carboxy-2-methylprop-1-yl)N-pentanoyl-N-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]amine of Formula I.

Valsartan is an angiotensin II antagonist acting on the AT1 receptor subtype. It is useful for the prophylaxis and treatment of diseases or conditions which may be inhibited by blocking the AT1 receptor, such as high blood pressure and cardiac insufficiency.
Processes for the synthesis of valsartan and its intermediates are provided in, for example, U.S. Pat. Nos. 5,399,578 and 6,271,375, U.S. Patent Application Publication Nos. 2006/0069268, and 2006/0100443 and Org. Process Res. Dev., 2007, 11(5) 892-898.
The compounds of Formula II and Formula VI are intermediates for the preparation of valsartan.

U.S. Pat. No. 5,399,578 provides a process for the preparation of the compound of Formula II by reacting a compound of Formula III
with the tosylate salt of Formula IV
in dimethylformamide in the presence of diisopropylethylamine. The reaction is carried out by stirring the reaction mixture at 80° C. for 1 hour. The compound of Formula II is further reacted with a compound of Formula V
in methylene chloride in the presence of diisopropylethylamine to obtain the compound of Formula VI. The reaction is carried out by stirring the reaction mixture at room temperature for 20 to 25 hours. The compound of Formula VI is finally reacted with tributyltin azide and deprotected to obtain valsartan.
U.S. Patent Application Publication No. 2006/0281801 provides a process for the preparation of the compound of Formula II by reacting the compound of Formula III and the tosylate salt of Formula IV in a solvent system containing toluene or xylene and water. The reaction is carried out by heating the reaction mixture to 50° to 55° C. for 25 hours in the presence of potassium carbonate and tetrabutylammonium bromide followed by acidification with hydrochloric acid to obtain the compound of Formula II as a hydrochloride salt with 97% purity. The hydrochloride salt of the compound of Formula II is converted to its free base form by treating with aqueous sodium bicarbonate in toluene. The compound of Formula II obtained as a free base is reacted with the compound of Formula V in toluene in the presence of diisopropylethylamine at 20° C. for 30 minutes to obtain the compound of Formula VI. The compound of Formula VI is isolated with 96% purity after acid-base treatments and layer separation.
Org. Process Res. Dev., 2007, 11(5) 892-898 discloses that the use of diisopropylethylamine in the preparation of compounds of Formula II and Formula VI leads to the formation of byproducts, including (S)-3-methyl-2-pentanoylamino-butyric acid benzyl ester of Formula VII and pentanoic acid anhydride of Formula VIII in 5 to 8 mol % each.

The Org. Process Res. Dev. reference further provides a process for the preparation of compounds of Formula II and Formula VI without using diisopropylethylamine. According to this process, the compound of Formula II is prepared by reacting the compound of Formula III with the free base form of the compound of Formula IV in xylene at 60° C. for 2 hours. The compound of Formula II is isolated as a hydrochloride salt from xylene solution by the addition of aqueous hydrochloric acid at 72° C. under vigorous stirring for 2 hours and by removing the water continuously by Dean-Stark distillation. The hydrochloride salt of the compound of Formula II is further converted into its free base form by stirring at 50° C. for 30 minutes in the presence of sodium hydroxide, water and xylene. The compound of Formula II obtained as a free base is reacted with the compound of Formula V in xylene in the presence of aqueous sodium hydroxide at 40° C. for 2 hours to obtain the compound of Formula VI. The compound of Formula VI is isolated by treating with ammonia solution, layer separation and distillation.
The processes provided in the Org. Process Res. Dev. reference for preparing the compounds of Formula II and Formula VI involve the use of high-boiling solvents like xylene or toluene. U.S. Patent Application Publication No. 2006/0281801 also involves the use of xylene or toluene for the preparation of the compound of Formula II. The use of high-boiling solvents requires high temperature conditions for the reaction. Carrying out these reactions at temperature conditions above 40° C. is likely to result into degradation of the products and requires employing further purification steps, which are lengthy and uneconomical. The processes provided in Org. Process Res. Dev. also require additional steps of converting the salt forms of the compounds for Formula IV and Formula II into their free base forms prior to further reactions. The processes provided in U.S. Pat. No. 5,399,578 and U.S. Patent Application Publication No. 2006/0281801 involve the use of diisopropylethylamine, which is reported to lead to the formation of impurities.